Developmental Defects in Mouse Embryos Lacking N-Cadherin

Abstract

To investigate the functions of N-cadherin in vivo, we have mutated the gene encoding this adhesion protein in mice. Although N-cadherin is expressed at the time of gastrulation and neurulation, both neurulation and somitogenesis initiate apparently normally in homozygous mutant embryos. However, the resulting structures are often malformed. The somites of the mutant embryos are small, irregularly shaped, and less cohesive compared with those of their wild-type littermates, and the epithelial organization of the somites is partially disrupted. Undulation of the neural tube is also observed in the mutant embryos. Homozygous mutant embryos die by Day 10 of gestation. The mesodermal and endodermal cell layers of the yolk sac are separated in the mutants. The most dramatic cell adhesion defect is observed in the primitive heart; although myocardial tissue forms initially, the myocytes subsequently dissociate and the heart tube fails to develop normally. In vitro studies of cardiac myocytes derived from N-cadherin mutant embryos show that the cells can loosely aggregate and beat synchronously, demonstrating that electrical coupling can occur between N-cadherin-deficient cardiac myocytes. These results show that N-cadherin plays a critical role in early heart development as well as in other morphogenetic processes.

Timing and kinetics of E‐ to N‐cadherin switch during neurulation in the avian embryo

“…These observations fully support previous genetic studies in the mouse and Zebrafish showing that, in the absence of N-cadherin, onset of formation of the neural epithelium develops normally. The first signs of neural tube malformations are detected relatively late, in the mouse, by the appearance of undulations along the neural tube after closure (Radice et al, 1997) and, in the fish, by the absence of cavitation due to alterations in movements of convergence and intercalation (Hong and Brewster, 2006). Therefore, rather than a prerequisite to the morphological changes, cadherin switch appears merely as a secondary event during neurulation.…”

“…In the chick embryo, the neural plate, from which the entire central nervous system is formed, is initially a flat epithelium of cuboidal cells that express E-cadherin and not N-cadherin. At completion of neurulation, when the neural tube is formed and fully separated from the superficial ectoderm, neural epithelial cells exhibit their typical elongated, radially-oriented shape and constitute a pseudo-stratified epithelium in which E-cadherin has been totally replaced by N-cadherin (Thiery et al, 1984;Hatta et al, 1987;Duband et al, 1988;Detrick et al, 1990;Radice et al, 1997). Yet, neural epithelial cells are unable to undergo spontaneous EMT; instead, they tend to remain coherent, even in two-dimensional culture where they retain their organization as a hollow tube (Duband et al, 2009).…”

“…This E-to Ncadherin switch during neurulation has often been interpreted as an event necessary both for the acquisition of the morphological features of neural epithelial cells and for the movements of neurulation to occur. However, despite a variety of experiments in different animal models that uncovered the importance of N-cadherin in early neural development (Bronner-Fraser et al, 1992;Radice et al, 1997;Lele et al, 2002;Hong and Brewster, 2006;Nandadasa et al, 2009), these hypotheses have never been tested experimentally, and the biological significance of the change in cadherin expression during neurulation remains, therefore, unclear. In particular, it is not known why, contrary to epithelial cell lines established in vitro, E-cadherin loss in the neural epithelium does not provoke EMT.…”

Cell biology of embryonic migration

“…Reduced migration, inability to undergo capillary morphogenesis in matrigel (Kondo et al, 2007) Total Mice viable, defects in retinal vasculature (Dimaio et al, 2008) β-catenin Cell-cell adhesion Conditional EC-specific knockout Death between E11.5 and E13.5; impaired vascular patterning in the head, vitelline and umbilical vessels, and placenta (Cattelino et al, 2003) N-cadherin Cell-cell adhesion Conditional NC specific Defects in remodeling of cardiac outflow tract (Luo et al, 2006) Total Death by E10 (Radice et al, 1997) Conditional EC specific Death at midgestation, severe vascular defects, decrease of VE-cadherin (Luo and Radice, 2005) E-cadherin Cell-cell adhesion Total Early lethality, fail to form trophectoderm. (Larue et al, 1994) VE-cadherin Cell-cell adhesion Total Death at E9.5, endothelial cells are assembled in vascular plexi, but their subsequent remodeling and maturation are impaired.…”

Zebrafish protocadherin 10 is involved in paraxial mesoderm development and somitogenesis

“…Cadherin 2 (Cdh2, N-cadherin) in developing somites has been studied in different animals. This molecule was localized to developing somites in chick and zebrafish embryos (Duband et al, 1987;Radice et al, 1997;Crawford et al, 2003). Administration of antibodies that perturb Cdh2-mediated adhesion to chick embryos resulted in disarranged or anomalous somites (Linask et al, 1998).…”